AB0808 A PROOF OF BIOLOGICAL CONCEPT TRIAL OF CM101 TO TARGET CCL24 IN SYSTEMIC SCLEROSIS: A BIOMARKER INFORMED, PRECISION MEDICINE APPROACH
Authors: F. Del Galdo, D. Khanna, C. Crater, R. Aricha, J. Lawler, A. Mor, I. Vaknin, M. Frankel, M. Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Systemic sclerosis (SSc) is an inflammatory and fibrosing autoimmune disease of unknown etiology. However, it has been established that endothelial cells, immune cells, and fibroblasts play important roles in SSc initation and progression. CCL24 (eotaxin-2) is a chemokine secreted by fibroblasts and endothelial cells, which promotes trafficking of profibrotic immune cells through the CCR3 receptor. Levels of CCL24 and CCR3 in the skin and serum of patients with SSc were found to be upregulated compared with healthy controls <sup>[1]</sup>. Serum CCL24 levels have been shown to correlate with extracellular matrix turnover biomarkers, to predict decline in forced vital capacity (FVC) and the diffusion capacity of the lungs for carbon monoxide (DLCO), and to be associated with a worse digital ulcer burden in patients with SSc <sup>[1]</sup>. Blockade of CCL24 with CM101, a humanized IgG1 anti-human CCL24 monoclonal antibody, significantly reduced endothelial cell activation in vitro and in skin and lung immune cell infiltration and fibrosis in experimental SSc animal models. <h3>Objectives</h3> To present an innovative trial design which allows for comprehensive disease assessment and determination of the biological activity of CM101 in patients with SSc. <h3>Methods</h3> Informed by the predictive value of CCL24 on vascular and fibrotic clinical outcomes in a large SSc observational cohort, the CM101 clinical development team aims to bridge biomarker science and clinical trial design by implementing a phase 2a clinical trial that includes evaluation of the biology of CCL24, effects of CCL24 blockade on biological and clinical markers of SSc activity, with comprehensive safety and efficacy assessments in patients with SSc. <h3>Results</h3> A biomarker driven, phase 2a, multicenter, randomized, double-blind, placebo-controlled, proof of biology study was designed to evaluate the safety, tolerability, and activity of CM101 in patients with SSc. Approximately 45 patients will be enrolled and randomized in a 2:1 ratio to receive either 10 mg/kg CM101 IV every 3 weeks (N=30 patients) or placebo (N=15 patients) for 8 treatments in the double-blind treatment period (24 weeks). All patients will have the option to receive 8 active treatments (CM101 20mg/kg IV every 3 weeks) in the open-label treatment period (24 weeks), with a follow-up period of 12 weeks. To elucidate the role of CCL24 in SSc, adults with early limited or diffuse cutaneous SSc are required to have elevated serum levels of CCL24 and clinical evidence of active disease, defined as modified Rodnan Skin Score (mRSS) ≥ 15 or presence of interstitial lung disease or current digital ulcer along with elevated C-reactive protein, erythrocyte sedimentation rate, or platelets, at trial entry. CM101 biological activity will be evaluated through a pre-defined biomarker analysis. Along with safety assessment, the clinical activity of CM101 on the vascular, dermatological, and pulmonary systems will be evaluated by nailfold video capillaroscopy, Digital Artery Volume index (DAVIX<sup>©</sup>), Digital Ulcer Clinical Assessment Score, mRSS, and FVC. The global response will be assessed by the revised Composite Response Index Systemic Sclerosis (CRISS) in conjunction with patient-reported outcomes. <h3>Conclusion</h3> This novel, biomarker enriched clinical trial, will determine the biological activity of CM101 in patients with active vascular or fibrotic SSc, across limited and cutaneous subsets, and inform future development of CM101 in SSc. Bridging biomarker science with clinical trial design carries the opportunity of improving the efficiency in subsequent clinical development and allows for a targetted treatment approach. <h3>References</h3> [1]Mor A, Segal Salto M, Katav A, et al. Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis. Ann Rheum Dis. 2019;78:1260-8. <h3>Acknowledgements</h3> Sean Gill for his input with clinical trial operations and Olga Kubassova, PhD for her input in imaging endpoint assessment. <h3>Disclosure of Interests</h3> Francesco Del Galdo Consultant of: Chemomab Therapeutics, Dinesh Khanna Consultant of: Chemomab Therapeutics, Christina Crater Employee of: Chemomab Therapeutics, Revital Aricha Employee of: Chemomab Therapeutics, John Lawler Employee of: Chemomab Therapeutics, Adi Mor Employee of: Chemomab Therapeutics, Ilan Vaknin Employee of: Chemomab Therapeutics, Matthew Frankel Employee of: Chemomab Therapeutics, Marco Matucci-Cerinic Consultant of: Chemomab Therapeutics.